When a dangerous virus emerges, one of the first questions scientists ask is whether it can cause severe disease or death. COVID-19 taught scientists that there is another question that can be just as important: What happens to those who survive?
Now, as H5N1 avian influenza continues circulating in birds and mammals, especially during migrations, researchers are asking an even more complicated question: What happens when an infection during pregnancy could affect not only one life, but two?
A new study involving Michigan State University veterinary pathologist Jack Harkema provides some of the first detailed answers in a laboratory model.
Researchers found that a strain of H5N1 isolated from dairy cattle could spread through the bodies of pregnant mice, infect the placenta and fetus and, when infection occurred later in pregnancy, reach newborn offspring through their mother’s milk. The offspring also showed developmental and behavioral changes that persisted after the initial infection.
The study, published in Nature Communications, establishes a new preclinical model researchers can now use to investigate how H5N1 affects pregnancy and to test potential ways to prevent or treat the disease.
“The very first thing is avian flu probably is not going to go away,” Harkema said. “It’s very crucial that we understand the disease and how to treat it way in advance.”
Harkema, a University Distinguished Professor in MSU’s College of Veterinary Medicine, collaborated on the study with researchers led by Sabra Klein, a virologist and immunologist at the Johns Hopkins Bloomberg School of Public Health.
Following the virus
Though H5N1 is best known for its impact on birds and other fowl, its spread into mammals — including dairy cattle — has increased interest in understanding how the virus behaves after crossing into mammalian hosts.
For the new study, researchers used H5N1 viruses isolated during outbreaks in dairy cattle in Texas and Ohio and developed a mouse model that allowed them to study infection during different stages of pregnancy.
When mice were infected at a stage roughly corresponding to the second trimester of human pregnancy, researchers detected infectious virus in the uterus, placenta and fetus.
But knowing the virus had reached the placenta wasn’t enough for Harkema.
As a veterinary pathologist, his role was to determine precisely where the virus was going — and what damage it was causing when it got there.
Researchers identified viral infection in trophoblasts, specialized cells in regions of the placenta that play critical roles in the exchange of nutrients and gases between mother and developing offspring.
That level of detail becomes particularly important when scientists begin testing treatments, Harkema said.
A therapy might successfully reduce the amount of virus or tissue damage in the lungs, for example, but fail to protect the placenta. By knowing which tissues and cells are affected, researchers can evaluate whether a treatment is protecting both mother and offspring.
A second route to offspring
When researchers infected mice later in pregnancy, they discovered another route of transmission. The virus reached the mammary glands and milk and was subsequently detected in nursing offspring.
The researchers then followed offspring after birth and found effects that extended beyond the acute infection, including developmental and behavioral changes.
For Harkema, those longer-term effects were among the study’s most surprising findings.
“They survived, right? But they had cognitive problems, and that was surprising to me,” Harkema said.
The finding connects the H5N1 research with another question Harkema and his collaborators have been investigating since the COVID-19 pandemic: What happens after the initial viral infection is over?
“Since COVID, we have more appreciation of long-term effects,” Harkema said. “That’s where a lot of studies are going — trying to understand what’s happening to the brain.”
Researchers caution that the behavioral effects could result from several factors associated with maternal infection and cannot simply be attributed to the virus directly infecting the offspring’s brains.
Why pregnancy matters
The study also addresses a longstanding gap in biomedical research: understanding how disease and potential treatments affect women during pregnancy.
Historically, many preclinical studies relied heavily on male animals. This research instead specifically examines pregnancy and the consequences of infection for both mother and offspring.
“Women’s health and pregnancy and offspring — we have to have even more studies like these to really understand how the viruses can affect the susceptible population,” Harkema said.
The researchers emphasize that results in mice cannot be assumed to occur in humans. Although mice provide scientists with well-characterized genetic and immune systems for studying disease, there are important biological and anatomical differences between mice and people, including differences in the placenta.
“A mouse is not a human,” Harkema said. “There are specific differences and a lot of similarities . . . but you have to translate those differences to humans.”
That is precisely why establishing and carefully characterizing the model is important.
Researchers can now use it to investigate different H5N1 variants and, ultimately, evaluate whether vaccines or therapeutics prevent the virus from spreading beyond the lungs and protect both mother and offspring.
“The next step is putting this model in use for developing specific drugs and investigating ways of reducing disease and transmission,” Harkema said.
Preparing before the next outbreak
For Harkema, the research is part of a larger scientific shift accelerated by COVID-19: preparing for emerging infectious diseases before they become widespread human health emergencies.
His own involvement grew out of decades of expertise studying how inhaled pollutants and other environmental exposures damage the respiratory system. Since the pandemic, that expertise has increasingly brought him into multidisciplinary teams studying SARS-CoV-2, long COVID and now H5N1.
Those collaborations combine virology, immunology, pathology and other specialties to understand not simply whether a virus causes disease, but where it travels, which cells it attacks, why some individuals are more vulnerable and what happens long after an infection. The H5N1 study adds pregnancy and the developing offspring to those questions.
Scientists cannot know whether H5N1 will eventually pose a substantially greater threat to humans. But Harkema said researchers should not wait for another public health emergency to begin answering fundamental questions about the disease.
“These type of studies really are creating more knowledge and understanding,” Harkema said. “We have to be prepared.”
And for pregnant women and their children in particular, he said, that preparation matters.
“If we don’t have the right vaccines, we don’t have the right treatments, they’re going to suffer and the whole society is going to suffer,” Harkema said. “This is just one piece, but it’s a very important piece.”
